The long term objective of this application is to understand how HIV evades the immune response and establishes a chronic infection. Insights into how this occurs may lead to new strategies to augment the ability of the immune response to eradicate the virus. One way that HIV avoids immune recognition is by reducing cell surface levels of major histocompatibility complex class I molecules (MHC-I), thereby protecting HIV-infected cells from recognition by cytotoxic T lymphocytes (CTLs). In addition, we have found that the capacity of cells to process and present antigens varies depending on the MHC-I haplotype and the cell type that is infected. Thus, we will pursue the following aims: (1) We will demonstrate that antigen presenting cells (APCs) and individual MHC-I molecules have unique pathways of antigen processing and presentation that (2) affect their responsiveness to Nef and recognition by CTLs. In addition, we will demonstrate that (3) HIV evades the immune response by remaining latent in long-lived progenitors of these cell types, which can serve as inducible reservoirs of HIV infection in vivo. To accomplish these goals we will use biochemical and cell biological methods to define the trafficking pathways of individual MHC-I molecules in normal and HIV- infected cells. We will also perform studies using patient samples to characterize the capacity of myeloid precursors to support HIV infection in vivo. This proposal is relevant to the mission of NIH in that it seeks to understand basic mechanisms of how HIV establishes a chronic infection. This work has the potential to have a significant impact on public health.